HLA Alleles and Type 1 Diabetes Mellitus in Low Disease Incidence Populations of Southern Europe: A Comparison of Greeks and Albanians

Abstract

Type 1 diabetes mellitus (DM1) is caused by environmental factors acting on genetically susceptible individuals. HLA-DQA1 and -DQB1 are major genetic determinants of the disease. Greece and Albania represent the low DM1 incidence countries of South-Eastern Europe. The HLA-DQA1 and -DQB1 associations with DM1 were investigated in these two groups, as reference for comparisons to the high-risk populations of Northern Europe. One hundred and thirty Greeks and 64 Albanians with DM1 were studied; 1,842 Greeks and 186 Albanians were analysed as controls. The samples were typed for six HLA-DQB1 alleles, using time-resolved fluorometry to detect the hybridisation of lanthanide labelled oligonucleotides with PCR products. Individuals positive for DQB1*0201 were selectively typed for three DQA1 alleles. In both populations DQB1*0201 increased the risk for DM1 while DQB1*0301 was protective. DQB1*0302 was associated with lower risk than *0201, while *0602 and *0603 were protective in Greeks but not in Albanians. It was also shown that DQA1 has a modifying effect, altering the risk conferred by the susceptible DQB1*0201. The low incidence of DM1 in these two countries correlates with the high frequency of the protective allele DQB1*0301 and the low impact of the susceptible DQB1*0302.

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

“…DQB1*0302 was strongly associated with, while DQB1* 030101 was largely protective of T1D. Similar associations were reported for northern Europe (8, 14-16), but not southern Europe (15,24) or Mediterranean countries (3), in which DQB1*0201 was reported as the major DQB1 susceptible allele. This lack of association of DQB1*0201 with T1D in Tunisians was supported by the finding that DQB1*0201 was linked with T1D susceptibility when present with DRB1* 030101 but was negatively associated with T1D when present with DRB1*070101 in a haplotype.…”

“…Accordingly, the enrichment or decreased prevalence of select DRB1-DQB1 haplotypes in T1D patients imparts disease susceptibility or protection, respectively (3,18,24). This susceptibility or protection effect disappears when a different DRB1 or DQB1 allele replaces the specific allele in the haplotype (29).…”

Influence of Common and Specific HLA-DRB1/DQB1 Haplotypes on Genetic Susceptibilities of Three Distinct Arab Populations to Type 1 Diabetes

“…Many T1D susceptibility loci have been described and have been mapped into the IDDM1 to IDDM18 loci, of which the HLA region (identified as IDDM1) accounts for more than half of the genetic susceptibility to T1D (2,16), whereas determination of a strong linkage disequilibrium between the DRB1 and the DQB1 alleles confirmed the contribution of specific HLA DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes to the presence of T1D in many ethnic groups (7,12,16). This was highlighted by the association of DR3-and DR4-containing haplotypes with T1D in Caucasians (8, 10) but not Asians, including Japanese and Koreans (3,9), in whom different haplotypes contribute to disease susceptibility (9).…”

“…In view of the strong association of HLA DRB-DQB haplotypes with T1D (6, 9, 16), coupled with their various distributions in different racial/ethnic populations (7,12,15,16), we investigated the association of HLA DRB-DQB haplotypes with T1D in individuals from three distinct Arab communities: Lebanon (Eastern Mediterranean), Tunisia (North Africa), and Bahrain (Arabian Peninsula). To avoid epidemiologic bias, only Arab subjects were included in the study; non-Arab nationals of the study communities, including Armenians (Lebanon), Berbers and Europeans (Tunisia), and Iranians (Bahrain), were excluded.…”

“…It is possible that the disease association conferred by DQB1‫-2030ء‬con-taining haplotypes is linked to the nature of the DRB1 allele contained in the haplotype. Alternatively, it may be due to racial considerations, highlighted by the pathogenic gradientlike nature of DQB1‫,2030ء‬ where DQB1‫2030ء‬ is linked with T1D in Northern European countries, including Finland (5, 6), but becomes neutral in Southern European and Mediterranean countries (12,14).…”